Process for preparing eprosartan

ABSTRACT

This invention relates to a process for preparing eprosartan by reacting 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid with (2-thienylmethyl)propanedioic acid, mono-ethyl ester.

This application is a 371 of International Application PCT/US98/02413,filed Feb. 13, 1998, which claims benefit from U.S. ProvisionalApplication 60/038,195, filed Feb. 14, 1997.

FIELD OF THE INVENTION

The present invention relates to a process for preparing eprosartan.This compound is described in U.S. Pat. No. 5,185,351 as being anangiotensin II receptor antagonist useful in the treatment ofhypertension, congestive heart failure and renal failure.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,185,351 describes processes for the preparation ofimidazole compounds. One of the processes described in this applicationis the reaction of an aldehyde with a substituted half-acid, half-esterderivative of a malonate. Although this process produces the imidazolesclaimed therein, there was a need to improve this process when preparingcompounds, such as eprosartan, on a commercial scale.

It has now been found that eprosartan can be prepared by reacting4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or thebisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid (PCTApplication WO 95/32189) with (2-thienylmethyl)propanedioic acid,mono-ethyl ester to produce eprosartan efficiently in high yield andhigh purity. The efficiency of this process and the quality and yield ofthe imidazole product are particularly important when preparing saidproduct on a large scale for therapeutic use.

DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation ofeprosartan, which is(E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoic acid, a compound of formula (I):

or a pharmaceutically acceptable salt thereof, which process comprisesreacting a compound of formula (II):

or an acid or a base addition salt thereof, with a compound of formula(III):

wherein R′ is C₁₋₄alkyl, at reduced pressure in the presence of acatalyst, such as piperidine or piperidinium propionate in an excess ofpropionic acid, and thereafter hydrolyzing the R′ ester and optionallyforming a pharmaceutically acceptable salt.

Alternately, a formula (I) compound can be prepared by reacting acompound of formula (IV):

with a formula (III) compound at reduced pressure in the presence of acatalyst, such as piperidine or piperidinium propionate in an excess ofpropionic acid, and thereafter hydrolyzing the R′ ester and optionallyforming a pharmaceutically acceptable salt.

Acid addition salts of formula (I) and (II) compounds are formed withthe appropriate inorganic or organic acids by methods known in the art.Representative examples of suitable acids are maleic, fumaric, acetic,succinic, hydrochloric, hydrobromic, sulfuric, phosphoric ormethanesulfonic. Preferably, the pharmaceutically acceptable acidaddition salt for the formula (I) compound is the methanesulfonic acidaddition salt.

Base addition salts of formula (I) and (II) compounds are formed withthe appropriate inorganic or organic bases by methods known in the art.Cationic salts are prepared by treating the parent compound with anexcess of an alkaline reagent, such as hydroxide, carbonate or alkoxide,containing the appropriate cation; or with an appropriate organic amine.Representative examples of cations are Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄⁺. The preferred salt form for the formula (II) compound is

As used herein, C₁₋₄alkyl means an alkyl group of 1-4 carbons, branchedor unbranched. C₁₋₄alkyl includes methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and t-butyl. The preferred R′ C₁₋₄alkyl group isethyl.

Typically the process is carried out by combining4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or thebisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid with(2-thienylmethyl)-propanedioic acid, mono-ethyl ester in a suitablesolvent, such as toluene, in the presence of a catalyst, for example, inthe presence of piperidinium propionate and an excess of propionic acid,at a suitable temperature, such as at a temperature of about 75° C. toabout 100° C., preferably at a temperature of 80° C.-85° C., at reducedpressure, such as at an internal pressure reduced to about 9-13 inchesof Hg, preferably 11 inches of Hg. The ester precursors to the formula(I) compound are hydrolyzed to the corresponding formula (I) carboxylicacid using base, such as aqueous sodium or potassium hydroxide.Thereafter, pharmaceutically acceptable salts may be prepared asdescribed above.

Alternately, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acidor the bisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and(2-thienylmethyl)propanedioic acid, mono-ethyl ester are reacted to give(E)-α-[[2-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoic acid by heating the two substrates in toluene at reflux underreduced pressure and in the presence of piperidine as catalyst followedby hydrolysis of the intermediate ester ethyl (ethyl(E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate).In this preparation,4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or thebisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid,(2-thienylmethyl)propanedioic acid, mono-ethyl ester, and toluene arecharged to a glass lined steel vessel and are initially heated to 55-60°C. to afford a homogenous solution. The catalyst (66 mol % piperidine)is added and the reaction is heated to reflux (70-75° C.) under reducedpressure. Reflux conditions are maintained for 20-35 hours andadditional (2-thienylmethyl)-propanedioic acid, mono-ethyl ester isadded. Once the reaction is complete, water and aqueous sodium hydroxideare added to the vessel and the reaction mixture heated at reflux underatmospheric conditions for 1-3 hours. The reaction is deemed completewhen the level of ethyl(E)-α-[[2-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate is less than 2.0%. The reaction is cooled to 45-50° C. andthe aqueous and organic phases separated. The toluene phase isdiscarded. Ethanol is added to the aqueous phase and the solution isacidified with aqueous hydrochloric acid until a pH of 5.0 to 5.4 isachieved, maintaining the temperature at 50-55° C. The product slurry iscooled and allowed to stir at 10-15° C. for 2 hours. The product isisolated by centrifugation, washed and stored. Thereafter,pharmaceutically acceptable salts may be prepared as described above.

The reaction between4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or thebisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and(2-thienylmethyl)propanedioic acid, mono-ethyl ester catalyzed withpiperidine can be run successfully in solvents (and/or solvent systems)other than toluene; these solvents include cyclohexane,cyclohexane:dichloroethane (12:5 or 1:1), cyclohexane:pyridine (12:5),and cyclohexane:ethyl acetate:pyridine (8:3:1).

Other catalysts which successfully promote the reaction between4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or thebisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and(2-thienylmethyl)propanedioic acid, mono-ethyl ester in toluene underreduced pressure besides piperidine include morpholine,1-methylpiperazine, and pyrrolidine.

The invention is illustrated by the following examples. The examples arenot intended to limit the scope of this invention as defined hereinaboveand as claimed hereinbelow.

EXAMPLES Example 1 Preparation of(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoic acid (Eprosartan)

Reagents and Solvents  1. Bisulfite addition compound of 12.03 kg  28.82moles   4-[(2-n-butyl-5-formyl-1H-   imidazol-1-yl)methyl]benzoic acid  (68.57% 4-[(2-n-butyl-5-formyl-1H-   imidazol-1-yl)methyl]benzoicacid)  2. (2-Thienylmethyl)propanedioic acid, 15.29 kg  54.18 moles  mono-ethyl ester (80.9% w/w assay)  3. Piperidine  2.85 L  28.82 moles 4. Propionic acid  8.60 L 115.28 moles  5. Toluene   56.5 L + 19.0 L =75.5 L total  6. Sodium hydroxide  16.7 kg 208.75 moles (50% aqueoussolution)  7. Water  65.0 L  8. Ethanol  41.2 kg  9. 6 N HCl Adjust topH 5.0 to 5.2 10. Water  75.0 L

Procedure

1. Charge toluene (56.5 L) to the reactor.

2. Charge (2-thienylmethyl)propanedioic acid, mono-ethyl ester (15.29kg, 80.9% w/w assay) and bisulfite addition compound of4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid (12.03 kg,68.57% 4[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) tothe reactor and initiate stirring. Reduce the internal pressure to 11inches of Hg and heat to reflux (internal temperature of reaction wasmaintained between 80-85° C.) for 1-2 h. Set the jacket temperature at110° C. Collect the water in a Dean-Stark trap.

3. Charge toluene (19.0 L) followed by propionic acid (6.45 L, 86.46mol) to a second reactor. Treat the resulting solution slowly withpiperidine (2.85 L, 28.82 mol) at room temperature. Stir the resultingmixture for approximately 30 min.

4. Vent the first reactor with nitrogen and reduce the jackettemperature to 80 C. Transfer the piperidinium propionate-propionic acidsolution in toluene from the second reactor to the first reactor. Reducethe internal pressure to 11 inches of Hg and heat to reflux (internaltemperature of reaction was maintained between 80-85° C.). Set thejacket temperature at 140° C. Collect the water in a Dean-Stark trap.

5. After 7.5 h, the amount of aldehyde(4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) remainingin solution was about 20% and the amount of(2-thienylmethyl)propanedioic acid, mono-ethyl ester remaining was about20%. An additional charge of (2-thienylmethyl)propanedioic acid,mono-ethyl ester (1.53 kg, 5.42 mole) was added at the 8.5 h mark.

6. After 13.5 h, the reaction was complete and the reaction was cooledto 70° C. (The amount of aldehyde remaining was about 5%.) Water (65.0L) and sodium hydroxide (16.7 kg; 50% w/w aqueous solution) was addedand the reaction was brought to reflux.

7. The reaction was refluxed for an hour. The reaction was assayed forthe presence of ethyl(E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate. If any is present, reflux for an additional half hour.Repeat assay.

8. Cool the solution to 60 C. Separate the layers and add ethanol (41.2kg) to the water layer. Slowly adjust the pH of the solution to 5.2 with6 N HCl (temp. 60° C.). The product will start to crystallize (temp. 60°C.). Cool to room temperature and stir for two hours. Filter and washthe product with water (2×37.5 L).

7. The solid was vacuum dried (9.44 kg, 77.2%).

Analytical Data

HPLC Column Zorbax SB-C18, 3.5 mm, 7.5 cm × 4.6 mm Column Temperature 40C. Flow Rate 2.0 mL/min Sample Preparation 8 mL of the reaction is blowndown with a stream of nitrogen and then dissolved in 2 mL of 50:50acetonitrile : water Injection Volume 2.0 mL Detection Wavelength 235 nmMobile phase A 0.1 M Ammonium acetate (pH = 6.7) Mobile phase B 50:500.1 M Ammonium acetate : acetonitile Gradient program From 0 to 10minutes, from 100% mobile phase A to 100% mobile phase B in a lineargradient, 5 minutes at 100% mobile phase B, then re- equilibrate for 5minutes at 100% mobile phase A Run Time 15 minutes Equilibration Time 5minutes Retention time 4-[(2-n-butyl-5-formyl-  4.81 min1H-imidazol-1-yl)methyl]benzoic acid (E)-α-[[2-butyl-1-[(4-  4.58 mincarboxyphenyl)-methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (2-thienylmethyl)-  4.13 min propanedioic acid,mono-ethyl ester ethyl (E)-α-[[2-butyl-1-  8.43 min [(4-carboxyphenyl)-methyl]-1H-imidazol-5- yl]methylene]-2- thiophene propanoate

Example 2 Preparation of(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophenePropanoic Acid (Eprosartan)

A glass-lined steel reaction vessel is charged with4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid,(2-thienylmethyl)propanedioic acid, mono-ethyl ester (about 1.9 molarequivalents relative to assayed4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid), andtoluene (about 6.3 g per gram of assayed4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) and heatedto 55-60° C. Piperdine (approximately 66 mol % relative to4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) is added.The reaction is then heated to reflux with azeotropic removal of waterunder reduced pressure so that an internal temperature of about 70-75°C. is maintained. The reaction is monitored by IPC 1 for thedisappearance of starting4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid. If >10% ofthe starting 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acidremains after 12-30 hours, additional charges of(2-thienylmethyl)propanedioic acid, mono-ethyl ester (0.10 equivalentsper charge relative to4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) may beadded and the reaction continued. When IPC 1 analysis indicates that thereaction of starting4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid isessentially complete (<10% remaining), the solution is cooled to about60-65° C. The cooled solution is treated with demineralized water (6.8 gper gram of assayed4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) and anaqueous, 6.7 N, solution of sodium hydroxide (about 2.0 ml of solutionper gram of assayed4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) and themixture is heated at reflux for about 1.0-3.5 hours. The reaction isassayed, by IPC 2, to confirm the complete conversion (<2.0%) toproduct. The solution is then cooled to about 50° C. and the layers areseparated. Ethyl alcohol (about 5.0 g per gram of assayed4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid) is added tothe aqueous phase and the pH is adjusted to about 5.0-5.4 with aqueous,6 N, hydrochloric acid solution. The resulting suspension is stirred atabout 10-15° C. for about 2 hours to complete precipitation. The productis isolated by centrifugation, washed twice with water and the wet cakeis used directly in the next step. The corrected isolated yield ofproduct at this stage is typically about 70-85%. Assay of a dried sampleof product on a w/w basis by HPLC versus a standard sample typicallyindicates a relative purity of about 97-99%.

Analytical Data

IPC 1

HPLC (Gradient)

Apparatus: The following equipment or its equivalent can be used:

Instrument Hewlett Packard, Model 1050

Pumping System Ternary, low-pressure mixing gradient pump, HP 1050

Injector Autosampler, HP 1050 Series

Detector UV, Variable wavelength, HP 1050 Series

Conditions:

Column Zorbax SB-C18, 7.5 cm×4.6 mm, 3.5 microns particle size,Manufactured by Rockland Technologies, Inc.

US Distributor: MAC-MOD Analytical, Inc.

Dilution Solvent 1:5 Acetonitrile:BPLC Grade Water

Eluent Organic: HPLC grade acetonitrile

Aqueous: 0.1 M Ammonium acetate (pH=6.7)

Mobile Phase Preparation Mobile Phase A=0.1 M Ammonium acetate

Mobile phase B=50:50; 0.1 M Ammonium Acetate:Acetonitrile

Detection Wavelength 235 nm, 0.1 AUFS

Flow Rate 2.0 ml/min.

Temperature 40° C.

Injection Volume 20 microliters

Analysis Time 20 minutes

Re-equilibration Time 6 minutes

Sample Preparation Approximately 30 mg (2 drops) of the reaction mixtureis weighed into a 25 ml volumetric flask and dried under a nitrogenstream. The volumetric flask is then filled to volume with dilutionsolvent. The sample is sonicated for 10 minutes and allowed to cool toroom temperature

Gradient Program 1.) Initial Solvent Composition-0% mobile phase B

2.) Linear Gradient from 0% to 100% mobile phase B in 10 minutes

3.) Hold at 100% mobile phase B for 5 minutes

4.) Linear Gradient from 100% to 0% mobile phase B in 5 minutes

5.) Re-equilibrate at 0% mobile phase B for six minutes.

IPC 2

HPLC (Gradient)

Apparatus: The following equipment or its equivalent can be used:

Instrument Hewlett Packard, Model 1050

Pumping System Ternary, low-pressure mixing gradient pump, HP 1050

Injector Autosampler, HP 1050 Series

Detector V, Variable wavelength, HP 1050 Series

Conditions:

Column Spherisorb SCX, 5 um, 250 mm×4.6 mm

Dilution Solvent 1:5 Acetonitrile:HPLC Grade Water

Eluent Organic: HPLC grade acetonitrile

Aqueous Buffer A: 11.5 g ammonium dihydrogenphos-phate dissolved in 1000mL water adjusted to pH 2.5 with phosphoric acid

Mobile Phase Preparation Mobile Phase A=200 mL Buffer A, 700 mL water,100 mL acetonitrile

Mobile phase B=200 mL Buffer A, 450 mL water, 350 mL acetonitrile

Detection Wavelength 235 nm

Flow Rate 2.0 ml/min.

Temperature 60° C.

Injection Volume 10 microliters

Analysis Time 20 minutes

Re-equilibration Time 5 minutes

Sample Preparation Transfer 20 mL of the IPC sample into a 50 mL beaker.Stir and, if necessary, add methanol (one to two mL) until the solutionis homogenous. Using a Pasteur-pipet, transfer four drops of theIPC-sample (50 uL) into a 25-mL volumetric flask. Dilute with 20 mL ofmobile phase B and sonicate for one minute.

Gradient Program 1.) Solvent Composition from 0 to 3 minutes: 0% mobilephase B

2.) Linear Gradient from 0% to 100% mobile phase B in one minute

3.) Hold at 100% mobile phase B for 16 minutes

4.) Linear Gradient from 100% to 0% mobile phase B in 5 minutes

5.) Re-equilibrate at 0% mobile phase B for 5 minutes.

It is to be understood that the invention is not limited to theembodiments illustrated hereinabove and the right to the illustratedembodiments and all modifications coming within the scope of thefollowing claims is reserved.

What is claimed is:
 1. A process for the preparation of eprosartan, acompound of formula (I):

or a pharmaceutically acceptable salt thereof, which process comprisesreacting a compound of formula (II):

or an acid or a base addition salt thereof, with a compound of formula(III):

wherein R′ is C₁₋₄alkyl, at reduced pressure from about 9-13 inches ofHg, in the presence of piperidine or piperidinium propionate and excesspropionic acid, and thereafter hydrolyzing the R′ ester using base andforming a pharmaceutically acceptable salt.
 2. The process according toclaim 1 wherein the formula (II) compound is


3. The process according to claim 1 wherein the pharmaceuticallyacceptable salt of the formula (I) compound is the methanesulfonic acidsalt.
 4. The process according to claim 1 wherein the pressure isreduced to 11 inches of Hg.
 5. A process for the preparation ofeprosartan, a compound of formula (I):

or a pharmaceutically acceptable salt thereof, which process comprisesreacting a compound of formula (IV):

or an acid or a base addition salt thereof, with a compound of formula(III):

wherein R′ is C₁₋₄alkyl, at reduced pressure from about 9-13 inches ofHg, in the presence of piperidine or piperidinium propionate and excesspropionic acid, and thereafter hydrolyzing the R′ ester using base andforming a pharmaceutically acceptable salt.
 6. The process according toclaim 5 wherein the pharmaceutically acceptable salt of the formula (I)compound is the methanesulfonic acid salt.
 7. The process according toclaim 5 wherein the pressure is reduced to about 9-13 inches of Hg. 8.The process according to claim 5 wherein the pressure is reduced to 11inches of Hg.